Efecto del calcitriol sobre la sintesis placentaria de citocinas pro- nflamatorias en la preeclampsia y regulación de CYP27B1 y CYP24A1 por TNF-IFN- IL-6 e IL -1

Abstract

Placenta is an important source and target of hormones that contribute to immunological tolerance in pregnancy. It is known that in preeclampsia (PE), the placenta 1,25-dihydroxyvitamin D3 (calcitriol) synthesis is low; whereas proinflammatory cytokines levels are increased. Since the association of proinflammatory cytokines and calcitriol has not been studied in human placenta, the aim of the present work was to investigate the effects of calcitriol upon TNF-, INF- , IL-6 and IL-1 human trophoblast cultured cells of PE women. In addition, effects these cytokines upon calcitriol metabolism were evaluated in placental cell cultures obtained from normotensive (NT) women. Placentas were obtained immediately after delivery by cesarean section from NT and PE women. Calcitriol effects upon cytokines in PE cell cultures were also determined by qPCR and ELISA. Similarly, cytokine effects upon calcitriol synthesis and degradation in NT cell cultures were evaluated by gene expression of CYP27B1 and CYP24A1 using qPCR. This study shows for the first time that cytokine expression genes decreased as the cells formed syncytia and that calcitriol inhibits TNF- and IL-6 expression in cultured placental cells obtained from PE pregnancies. Controversely, TNF-, INF-, IL-6 and IL-1 increased expression of CYP27B1 and CYP24A1. Interestingly, TNF- increased significantly the ratio of CYP24A1/CYP27B1 gene expression, while IFN-  preferentially induced CYP27B1 over CYP24A1. No changes were observed when equimolecular concentrations of IL-1 and IL-6 were used. Results indicate interrelationships between calcitriol metabolism and cytokines production in the human placenta and suggest that INF- contributes to calcitriol production whereas TNF- favors its catabolism